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Brigham Offers Cutting-Edge Trials for Patients With AFib

Source: Brigham and Women's Hospital
Date: 1/11/2023
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For patients with atrial fibrillation (AFib), catheter ablation using cold or heat has been the standard of care for about 20 years. Today, thanks to improvements in mapping and other technologies, this procedure is more effective and safer than ever.

While this technique has benefited many patients, further improvements are still needed. The procedure can take several hours, is associated with about a 2% complication rate, and requires adjunctive medications or a repeat procedure in approximately 15% to 20% of patients.

Clinical investigators at the Brigham and Women’s Hospital Cardiac Arrhythmia Service are participating in several clinical trials seeking to develop new, cutting-edge techniques with the potential to benefit more patients. The service, led by cardiologist and electrophysiologist William Henry Sauer, MD, is known worldwide for its expertise in evaluating and treating a wide range of abnormal heart rhythms affecting various patients, particularly those with complex medical concerns.

Dr. Sauer credits Jorge E. Romero, MD, who was recently recruited as director of Arrhythmia & Electrophysiology Research in the Division of Cardiovascular Medicine, for being instrumental in expanding the AFib research portfolio. Dr. Sauer adds that a team-based approach has meant that every member of the Cardiac Arrhythmia Service has contributed to the success of the research programs.

Using Pulsed Field Ablation for Pulmonary Vein Isolation

Among the trials currently active is the AdmIRE study, which uses pulsed field ablation for pulmonary vein isolation to treat people with symptomatic paroxysmal AFib. This technique incorporates high-voltage electricity to electroporate the cardiac muscle cells without requiring extreme temperatures.

“A lot of the complications associated with current ablation procedures are due to the effects of the heat or cold on adjacent structures,” Dr. Sauer says. “These procedures can sometimes cause injury to the esophagus or the phrenic nerve. But with pulsed field ablation, these structures are protected because they’re more resistant to that electroporation compared to the heart tissue.”

Since performing the first pulsed field ablation procedure at the Brigham in September 2022, the team has treated 20 more patients.

“My early experience with this technology is that the procedure is much faster. Patients feel great afterward, and they go home the same day without any problems,” Dr. Sauer says. “Although we have confirmed the procedure’s safety in the short term, more time is needed before we can determine its efficacy in the long term.”

Clinical Trials Offer New Approaches for Patients

Dr. Sauer and his team plan to participate in several other trials related to AFib. One of these, the ADVANTAGE AF Study, will explore the safety and effectiveness of an alternate pulsed field ablation system in patients with drug-resistant, symptomatic persistent AFib. Dr. Sauer expects that the trial will begin treating patients at the Brigham in December 2022.

Another study, the STAR AF3 trial, seeks to address a problem seen across all ablation techniques: The sites that are the source of AFib may be outside the areas around the pulmonary veins that are usually the target of ablation. This trial will evaluate a mapping technique to identify the appropriate areas to be ablated.

Mapping technology is important because it allows physicians to detect repeating patterns by analyzing electrocardiogram data. “These systems guide us toward those patterns that may be causing atrial fibrillation,” Dr. Sauer says. “What all of this research has in common is that it’s focused on leveraging different types of new technology.”

Cardiac Arrhythmia Service Moves the Field Forward

Collaboration is vital across the Cardiac Arrhythmia Service. The service includes a diverse team of specialists with expertise in all areas of cardiac care, including cardiologists, surgeons, inpatient and outpatient care teams, technicians, and nurses. Patients, including those with underlying medical conditions, can benefit significantly from the range of expertise.

“In addition to receiving treatments that have the potential to improve outcomes and are not yet available elsewhere, patients who participate in clinical research at the Brigham make important contributions to science and move our field forward,” Dr. Sauer says. “We are grateful to them for that.”

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Brigham Leads Development of Surgical Techniques for Treating AVM

Source: Brigham and Women's Hospital
Date: 1/9/2023
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The treatment for brain arteriovenous malformation (AVM) consists of observation, surgery, stereotactic radiosurgery, or endovascular embolization—either on its own or before surgery to remove the AVM. But these techniques don’t always yield a safe cure for patients, most of whom are young and experiencing debilitating symptoms.

Brigham and Women’s Hospital created the AVM Program, directed by neurosurgeon Nirav J. Patel, MD, to address this challenge and look for better solutions. The program is made up of cerebrovascular neurosurgeons, neuro-interventional radiologists, and vascular neurologists who collaborate on the development of interdisciplinary approaches. The team’s goal is to provide the best possible nonsurgical and surgical treatment options for people with AVMs.

“We at the Brigham started this program to help cure patients,” Dr. Patel says. “They often show up on our doorstep years after their initial diagnosis with a lot of misinformation. When someone in their teens or 20s is told they have a ticking time bomb in their brains, it’s very hard for them to hear. When we tell them we can cure them, they are shocked.”

Providing the Best Outcomes for Patients

Dr. Patel’s primary focus is a surgical technique that involves sealing off the feeding arteries to the AVM with clips before surgical resection (in other words, a surgical embolization), rather than blocking the arteries by endovascular embolization. “By using this AVM technique, we avoid the risks and costs of endovascular embolization,” he says. “The procedure takes longer and requires much more practice and surgical skill, but it often delivers better patient outcomes.”

After being trained in the technique by neurosurgeon Michael Morgan, AO, in Australia, Dr. Patel brought this approach to the Brigham. He’s made it his mission to offer the procedure to anyone who could benefit from it and train others to perform this delicate operation.

Toward that end, he sees the training of residents and fellows as an especially important role. “Everyone is expected to improve their microsurgical techniques,” he says. “It’s nothing special, just a lot of hard work that gets them there.”

Dr. Patel has built a 3D skills lab where trainees can practice working with brain blood vessels safely and perform bypass and repair. Training is done initially under a microscope with plastic tubes that simulate blood vessels. Dr. Patel also leads a preclinical rodent lab where residents and fellows can further hone their surgical techniques.

Creating Programs to Help AVM Patients Internationally

Many of Dr. Patel’s former trainees have taken the techniques with them upon moving on to faculty positions as far away as Japan, as well as to Puerto Rico and other parts of the United States.

Dr. Patel and his team have also traveled internationally to train local surgeons and provide care for patients unable to travel to the Brigham for surgery. In the summer of 2022, he journeyed to Paraguay, where he performed surgery on three patients. The trip was made in collaboration with the charity Solidarity Bridge—including the group’s program director, Lindsey Douchette, MPA, and neurosurgeon Richard Moser, MD—and neurosurgeon José Kuzli, MD, at the Hospital Nacional de Itaugua in Asuncion. Brigham anesthesiologist Grace Youngsook Kim, MD, and scrub nurse Carlos Vazquez accompanied Dr. Patel, with Vazquez also serving as a translator for Spanish-speaking patients.

“In addition to helping these patients, I shared my techniques with surgeons from all over the country who came to learn,” Dr. Patel says. “For countries like Paraguay that don’t have the instrumentation and resources to perform presurgical embolizations, teaching this procedure can make a profound difference in the lives of many patients with AVM. Our goal is to create a program there that is self-sustaining.” Dr. Patel had previously traveled to Puerto Rico, where he performed two AVM procedures and helped set up a similar program.

In the United States, Dr. Patel works with insurance companies to help patients out of network obtain coverage for treatment at the Brigham. He recently treated a 29-year-old mother of four from Chicago who experienced debilitating side effects after several failed embolizations.

A Continued Focus on Research

Dr. Patel notes that the role of the AVM Program is not only to develop new surgical techniques but also to refine all treatments that can benefit patients. This includes research in animal models to understand cerebral physiology and neuronal regeneration.

“We’re hoping to find a molecular marker for AVM that we can target and treat through medical means,” he says. “We’re working on sensitization of the endothelium inside the arteries. Eventually, we may be able to give patients a pill that makes their arteries selectively sensitive to radiation.” This might eventually provide another good treatment option for patients who cannot have surgeries like the ones that Dr. Patel performs.

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Botox Injections Aid in Surgery to Repair Hernias in Abdominal Wall

Source: Brigham and Women's Hospital
Date: 11/15/2022
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For some patients, surgery to cut and release the abdominal wall muscles may be necessary to fully repair complex ventral hernias. But select patients may benefit from a technique that employs injections of botulinum toxin A (Botox) to relax the abdominal muscles before surgery, enabling the surgeon to repair these large hernias less invasively.

Eric G. Sheu, MD, PhD, section chief of Bariatric and Foregut Surgery and a member of the Complex Hernia Center at Brigham and Women’s Hospital, has performed several of these procedures. They have allowed complex hernia repairs to be performed via a minimally invasive, robotic approach and have been well-tolerated by patients.

“There’s been a movement in hernia repair to really close the muscle tears completely, which we know provides the best outcomes for patients,” Dr. Sheu says. “By giving Botox injections before surgery to relax the lateral abdominal wall muscles, we’re able to create the laxity that allows us to restore a patient’s abdominal wall anatomy and core function.”

A New Option for Repairing Mid-sized Hernias

For smaller ventral hernia repairs, the muscles can usually be brought together with no additional procedures. For very large repairs, meanwhile, more complex surgery to release the muscles may still be needed.

“The Botox technique seems to work best when you’re in that middle zone, where the muscles are a bit too contracted laterally to come together, but where a more invasive procedure may not be needed,” Dr. Sheu says. “For medium-sized hernias, particularly in patients who have had a recurrence, this can be a very good option.”

This approach is still relatively uncommon, but several studies have found that Botox injections result in changes to the abdominal wall that make hernia repair surgery less complicated and more effective.

“As far as recovery from this procedure goes, it still may be more difficult than what you would have for a simple hernia, but not having to do the surgical release certainly makes it easier for patients,” Dr. Sheu says. “These procedures can often be done on an outpatient basis or require only a one-night hospital stay, compared with these more complex surgeries that usually require at least a couple of nights in the hospital.”

A Partnership Between Surgery and Radiology

This procedure requires a partnership between surgery and radiology. It includes imaging to determine which patients are most likely to benefit from the procedure as well as the involvement of an interventional radiologist who performs the Botox injections under the guidance of either ultrasound or CT.

Patients receive the injections two or more weeks before surgery to allow their muscles to relax fully. They receive a total of six injections, three on each side of the abdomen.

Daniel I. Glazer, MD, medical director of CT and director of Cross-Sectional Interventional Radiology at the Brigham, collaborates with Dr. Sheu on these procedures to ensure optimal placement of the Botox injections.

“As interventional radiologists, we’re well-positioned to do this type of procedure. We understand the anatomy and have the ability to accurately place the needles where they need to go,” Dr. Glazer says. “This collaboration allows us to work on a fairly innovative technique and help patients avoid more complex, invasive surgeries. It’s better for the patients both in terms of having a successful procedure and reducing morbidity.”

Innovative Care for Patients With Complex Hernias

This procedure is just one of the many novel approaches being offered to patients through the Brigham’s Comprehensive Hernia Center. The center includes board-certified general and gastrointestinal surgeons who have expertise in diagnosing and treating all types of hernias, including those that are very large, very complex, or recurrent. Experts in the center are skilled in the full range of hernia surgeries, including open, minimally invasive, and robotic surgical techniques.

The team also includes board-certified plastic and reconstructive surgeons who excel in complex abdominal wall reconstruction when direct closure is impossible and experts in wound healing who can help optimize cosmetic outcomes.

In addition to performing hernia repair surgeries, the center helps patients address any factors that could prevent a successful surgery and recovery. These include guidance in smoking cessation, a diabetes management program, and help with weight loss to reduce the chances of developing another hernia.

“We created this center to ensure that patients get all the medical and surgical care needed to have the best outcomes for their hernia repair,” Dr. Sheu says.

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STUDY FINDS DRUG BENEFITS HEART FAILURE PATIENTS WITH NORMAL EJECTION FRACTION

Source: Brigham and Women's Hospital
Date: 10/20/2022
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Over the past 20 years, the field of cardiology has made tremendous strides in advancing treatments for patients with heart failure who have a low ejection fraction (at or below 40%). But for heart failure patients with only mildly reduced or preserved ejection fraction (above 40%), developing effective therapies has proven more challenging.

Now that’s finally changing. An international, multicenter team led by Brigham and Women’s Hospital investigators has reported findings from the largest-ever study to look at whether these patients could benefit from treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin.

The randomized, placebo-controlled trial, which was published online in the New England Journal of Medicine (NEJM) in August 2022 and simultaneously presented at the European Society of Cardiology Congress, found that dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 18% in heart failure patients with all ejection fractions.

“What was most novel about this finding was that in addition to showing an overall benefit, we saw consistency of outcomes across all groups, including patients at the lower and upper ends of the ejection-fraction spectrum and in those patients enrolled in a hospital or recently hospitalized,” says first author Scott David Solomon, MD, the Edward D. Frohlich distinguished chair and professor of Medicine at Harvard Medical School and the director of the Brigham’s Clinical Trials Outcomes Center. “This study suggests that SGLT2 inhibitors should be a foundational therapy for all patients with heart failure, regardless of ejection fraction or care setting.”

Expanding SGLT2 Inhibitors Beyond Diabetes Care

Dapagliflozin and other SGLT2 inhibitors were originally developed as treatments for type 2 diabetes. The drugs work primarily through the kidneys, causing an increase in the excretion of both glucose and sodium in the urine. But investigators observed that patients taking these drugs had fewer cardiac events, leading to the study of these drugs in patients with heart failure.

In 2020, dapagliflozin was approved by the FDA for treating heart failure in patients with low ejection fraction, regardless of whether they had diabetes. Other SGLT2 inhibitors have also shown success in treating heart failure. But how this family of drugs functions in this context is not well understood.

“There is a lot of room for debate as to the exact mechanism by which SGLT2 inhibitors reduce the risk of heart failure, beyond their effects on the kidneys,” Dr. Solomon says.

Improving Care for a Range of Heart Failure Patients

The trial, known as DELIVER, randomized 6,263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive either 10 mg of dapagliflozin or a placebo once a day. Patients were treated in 20 countries throughout North and South America, Europe, and Asia. Coordination of and data analysis for the trial were led by investigators at the Brigham and at the University of Glasgow, with whom the Brigham has a longstanding collaboration.

After a median follow-up of 2.3 years, the researchers found that daily dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 18%. The drug also improved participants’ symptoms and quality of life, independent of whether they had diabetes. The side effects of the drug were low. Urinary tract infections, one of the most common side effects, were treatable and not severe.

Dr. Solomon hopes that based on the findings, the FDA will approve the drug for a broad range of heart failure patients.

Broader Data Analysis Provides More Study Details

At the same time the NEJM study was published, Dr. Solomon and his colleagues, including Brigham cardiologist Muthiah Vaduganathan, MD, MPH, also published a paper in The Lancet that was a meta-analysis of five randomized, controlled trials of SGLT2 inhibitors in patients with heart failure, including from the DELIVER trial.

That analysis, which comprised a total of 21,947 trial participants, found that SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalization for heart failure by 20%. “Although these findings are important, we have not cured heart failure,” Dr. Solomon says. “Even patients who received this therapy had a fairly high rate of events. Much more work needs to be done to reduce the risk in patients with heart failure.”

Dr. Solomon and his collaborators plan to continue analyzing the data from the DELIVER trial to learn more about how dapagliflozin works and who can benefit. “When you have a trial that enrolls more than 6,200 patients, you want to learn as much as you possibly can from it,” he concludes.

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Can a Fatty Acid Supplement Benefit People With Obesity and Prediabetes?

Source: Brigham and Women's Hospital
Date: 10/4/2022
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Obesity is a vast and growing health problem that negatively affects many systems in the body. It also increases the risk of diabetes, fatty liver disease, and cardiovascular disease, among other conditions.

Investigators at Brigham and Women’s Hospital are now looking at novel ways to boost the natural mechanisms that the body uses to counteract the development of obesity and its related complications. An upcoming clinical trial will explore whether dietary supplementation with palmitoleic acid (POA)—a monounsaturated fatty acid that is released by fat tissue during the metabolic process and part of the modern diet—can enhance key health measures in individuals who are obese and prediabetic.

In the lab, POA appears to reduce the accumulation of fat in the liver, improve the body’s sensitivity to glucose, and decrease inflammation in the vascular vessels.

“POA is a molecule that is part of the body’s own rescue system,” says physician-scientist Mehmet Furkan Burak, MD, an endocrinologist at the Brigham and instructor at Harvard Medical School, and a basic scientist in the Department of Molecular Metabolism within the Harvard T.H. Chan School of Public Health. “From an endocrinology standpoint, we want to see if we can mimic the body’s own rescue mechanism to tackle obesity-related problems.”

Harnessing the Body’s Natural Mechanisms

Researchers have known that when it comes to dietary fat, quality is more important than quantity for maintaining good metabolic health. This is where the idea of “healthy fats” comes from. But studies looking at supplementing the diet with so-called healthy fats like fish oil have had mixed results. One reason is that these oils contain a mixture of fatty acids, some of which may be beneficial and others of which are neutral or even detrimental.

POA is a key component of macadamia nut oil, which has been studied for its potential benefits. But in addition to high levels of POA, this oil also contains significant levels of palmitic acid, another fatty acid, which counteracts POA’s beneficial effects. A technique that allows the purification and separation of clinical-grade POA from other fatty acids is one thing that has made this new trial possible.

The discovery that POA could be a good candidate for boosting the body’s metabolism of fat came from laboratory studies by the Harvard T.H. Chan School of Public Health team, led by Gökhan S. Hotamisligil, MD, PhD (published in Cell in 2008). That research found that POA is an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses fat accumulation in the liver.

Later work in mice revealed that POA could have beneficial health effects in disease models. “This molecule goes to the muscle and improves insulin sensitivity. It goes to immune cells and makes them less inflammatory. It also decreases fat formation,” Dr. Burak says. “If we supply it from the outside in patients, can it lead to the same therapeutic improvements?”

A Unique, Placebo-controlled Trial Involving POA

Dr. Burak’s trial, which is expected to begin recruiting patients in November 2022, will be the first to look at supplementation with POA in people who are obese and prediabetic. The investigators plan to screen 120 individuals to ensure a distribution of individuals across the spectrum of glucose tolerance, ultimately enrolling 40 in the trial. Half of the participants will receive POA, with the other half receiving a placebo.

The primary measure of the trial will be POA’s effects on insulin sensitivity. The patients will also receive liver MRIs and DEXA scans. A key factor enabling this study is the ability to measure insulin sensitivity with the hyperinsulinemic euglycemic clamp test. “This high-end technique is the gold standard for testing insulin sensitivity. It’s not a calculation using a surrogate but is really the quantitative measurement,” Dr. Burak says. “Very few centers in the world can do this test.”

There will also be a lab component to this study in collaboration with Pau Sancho-Isabel Graupera of the Hospital Clínic de Barcelona. This research will investigate the molecular mechanisms of POA treatment on human liver organoids.

“If this trial proves successful, there are many implications for treating obesity-related complications,” Dr. Burak concludes.

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Making Headway in Targeting Glioblastoma Multiforme

Source: Brigham and Women's Hospital
Date: 6/14/2022
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The past two decades have seen considerable progress in developing targeted therapies for cancer. Many of these drugs are successful in treating both primary tumors and metastases. Additionally, when patients develop resistance to certain therapies, often other targeted treatments and new options are available.

Unfortunately, advances in precision oncology for glioblastoma multiforme (GBM) have lagged behind many other cancers. A multicenter, philanthropically funded effort now aims to address that deficit. Break Through Cancer is a foundation that brings together several elite cancer research centers to accelerate research through collaboration, conduct clinical trials, and ultimately develop cures for the deadliest cancers. One of those cancers is GBM.

Along with colleagues at the Dana-Farber Cancer Institute (DFCI), as well as investigators at the MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Johns Hopkins Medicine, and Massachusetts Institute of Technology, a team from Brigham and Women’s Hospital has been assembled to work on these efforts.

Conducting Serial Biopsies of the Brain

One reason for the disparity in available targeted therapies for GBM is the difficulty in obtaining regular biopsies of these tumors due to their location in the brain. Biopsies are a crucial part of targeted therapy.

“For decades we have run multiple trials for GBM, and none of them have been very successful,” says Nathalie Y. R. Agar, PhD, founding director of the Surgical Molecular Imaging Laboratory in the Brigham’s Department of Neurosurgery. “What many of us in the field have realized is that the main difference in treating other cancers is that, as part of clinical trials, patients undergo biopsies to assess the response of the tumor to the therapeutic agent under investigation.”

“Patients routinely receive multiple biopsies throughout the course of treatment for other cancers or other diseases to see whether drug X or drug Y actually is doing what it’s supposed to do,” adds E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery. “But we’ve never done that for GBM. This is what we’re proposing to do.”

Treatment With a Modified Oncolytic Virus

Because of the logistical and ethical issues surrounding the repeated collection of biopsies that require drilling into the skull, this research is being conducted in conjunction with a clinical trial that also requires direct access to the brain—delivery of an oncolytic virus that aims to destroy GBM tumors.

This treatment, in which a modified herpes simplex virus 1 is injected directly into the tumor, has already been tested in a phase 1 clinical trial at the Brigham and DFCI that enrolled 50 patients between 2017 and 2022. The treatment appeared to be safe and provided benefit to some patients.

The new research, an extension of the earlier trial, will enroll 12 more patients (three at each of the four Break Through Cancer-funded clinical institutions) to receive up to six doses over a four-month period. At the same time the patients receive the treatment, a biopsy of their tumor will be collected to assess how the cancer is responding.

“This treatment requires only conscious sedation and is guided by a GPS-like robotic system,” Dr. Chiocca says. “It’s very well tolerated, and most patients go home the next day.”

The hope is that by regularly collecting tumor tissue, researchers will be able to learn more about the mechanisms that underlie the cancer’s response to treatment, potentially leading to more personalized approaches as well as new, more effective therapies.

Looking at Combination Treatments

Eventually, the investigators plan to conduct additional trials in which other agents that require intratumoral injection are used. This next phase is likely to include a biologic agent that triggers the immune system to fight cancer.

Dr. Agar noted that this research has a strong translational science component, including the development of new model systems that will help investigators select new drugs or combinations of drugs that may also be effective.

“This work has been possible not only because of Break Through Cancer, but thanks to strong leadership at both the Brigham and DFCI,” she says. “We hope that it eventually will revolutionize the way that GBM is treated.”

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Brigham Researchers Investigate Lithium’s Effects on the Brain

Source: Brigham and Women's Hospital
Date: 6/23/2022
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Lithium has been used as a treatment for bipolar disorder for decades, but very little is known about its mechanism of action in the brain. While many newer drugs have been developed to treat the condition, lithium remains a mainstay for the treatment of bipolar disorder and other psychiatric illnesses in psychiatry’s toolbox.

Investigators at Brigham and Women’s Hospital are now using brain imaging and laboratory research to examine precisely how lithium affects the brain at the molecular, neuronal, and brain-circuit levels. They are also studying how it may actually increase the growth of certain areas of the brain and influence the organ at a structural level.

“Lithium has been shown to be very effective at treating bipolar disorder and reducing the incidence of suicide in certain populations,” says Amit Anand, MD, a psychiatrist at the Brigham. “At the same time, it’s very interesting because it’s a chemical element. Most medications belong to a class made up of similar drugs, but there is really nothing else like lithium.”

Correlating Gene Expression and Brain Changes

In a study published in Translational Psychiatry in April 2020, Dr. Anand and colleagues collected MRI scans and blood samples from 21 people with bipolar disorder before lithium treatment and at two and eight weeks after treatment. As a control, they also collected matched samples from 16 healthy, untreated individuals.

The research showed that after eight weeks of lithium treatment, the subjects had significant increases in gray matter fraction, global cortical thickness, and the thickness of frontal and parietal cortices. Volume increases were also seen for putamen, hippocampus, thalamic nuclei, and thalamic substructures.

Additionally, several genes showed significant expression changes; nine out of 14 pathways that were identified as being affected by lithium correlated significantly with the structural changes that were observed. These findings corresponded with lab research showing that lithium can boost the growth of neurons and suggest that lithium may also be useful in treating other diseases such as neurodegenerative disorders.

“Lithium goes inside neurons and has a direct effect on DNA and gene expression, particularly on neurotropic genes that help the growth of neurons,” Dr. Anand says. “We can correlate those changes with what we see happening on brain scans. This gives us more power to identify the changes in those genes, which would help in the development of other novel treatments for bipolar disorder and other psychiatric illnesses for which lithium has been found to be useful.”

Expanding Efforts to Find Drugs for Depression

Dr. Anand and his colleagues are now launching a new study to get a closer look at these effects. The National Institutes of Health has funded a larger trial that will include not only structural and functional brain scans, but also analysis of blood samples to look for changes in gene expression. Patients with bipolar disorder who are not currently taking any medications are eligible to participate. The patients will be treated with lithium and followed for six months.

“We’re using the Brigham’s 7-Tesla scanner, which is the strongest scanner approved by the U.S. Food and Drug Administration for use in human subjects and is very sensitive at picking up signals from the brain,” Dr. Anand says. “We plan to use resting-state brain connectivity and diffusion tensor imaging to look at the white matter fibers in the brain to see the changes after short- and long-term lithium treatment.”

In the future, the team plans to do similar kinds of studies looking at how other drugs, such as ketamine, affect brain structure in people who are being treated for treatment-resistant depression.

“There’s also a lot of interest in using psychedelics and MDMA to treat depression,” Dr. Anand says. “It’s important to establish experimental paradigms to do this kind of translational research and develop a deeper understanding of how these treatments work.”

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Translating Discoveries Into Better Treatments for IBD

Source: Brigham and Women's Hospital
Date: 5/16/2022
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Current treatments for inflammatory bowel disease (IBD) can help manage the disease’s effects, but improved treatments are desperately needed. To develop those treatments, it’s important to understand the underlying biological causes that drive different forms of IBD, including Crohn’s disease and ulcerative colitis.

Scott B. Snapper, MD, PhD, a physician-scientist in the Crohn’s and Colitis Center within the Division of Gastroenterology, Hepatology and Endoscopy at Brigham and Women’s Hospital, has devoted his research to this topic—both in the lab and the clinic. His current work focuses on determining the causes of IBD and employing novel animal models as well as direct human studies, including early-stage clinical trials, to study it.

“Since I began my research career, my goal has always been to better understand these diseases,” says Dr. Snapper, who trained as a microbiologist and immunologist in addition to training as a gastroenterologist. “All of that work has been leading up to developing new therapeutics.”

Mouse Models Reveal Disease Mechanisms

When Dr. Snapper started his research, there was a need for better animal models for studying IBD. One reason was that most cases of IBD are caused by numerous genetic factors. He realized that by studying the rare cases caused by single genes, he could pull apart the mechanisms that contribute to these conditions in more common cases as well.

“We use these rare examples to help us understand the cellular and molecular mechanisms and the host-microbial interactions that occur in all people who get Crohn’s disease and ulcerative colitis,” he says.

The first mouse model he worked with was one for Wiskott-Aldrich syndrome, a rare monogenic disease characterized by abnormal immune system function, among other issues. All the mice with the disease developed IBD. Today, there are more than 60 mouse models for studying different forms of IBD.

The Snapper Laboratory employs a number of basic, translational and clinical research strategies to understand and define not only the constituents but also the mechanisms that regulate intestinal homeostasis as it pertains to gastrointestinal health and IBD. Among the ongoing projects in his lab are the study of intestinal epithelial cells, immune cells and cytokines as well as translational work using humanized mice. This research is laying the foundation for the development of clinical trials.

Decoding the Underlying Causes of IBD

Among the findings that have come out of Dr. Snapper’s lab are that some cases of IBD presenting in very young children are caused by the absence of the interleukin-10 receptor.

“Patients lacking this receptor make a lot of the cytokine interleukin-1,” says Dr. Snapper, who is also chief of the Division of Gastroenterology, Hepatology and Nutrition and director of the Inflammatory Bowel Disease Center at Boston Children’s Hospital. “We’ve shown in early studies that in these patients, you can ameliorate much of their disease by blocking interleukin-1.”

Dr. Snapper says that this treatment has served as a bridge to offering bone marrow transplants for children with this rare immunodeficiency syndrome. He also notes ongoing efforts to identify subsets of all IBD patients with an enhanced interleukin-1 signature who might benefit from IL-1 blockade.

Research employing several mouse models of IBD, including the murine model of the Wiskott-Aldrich syndrome, has revealed another underlying mechanism of IBD, this one related to regulatory T cells.

“We’ve found in a novel humanized mouse model of IBD that you can expand regulatory T cells by giving low doses of interleukin-2 and improve disease,” Dr. Snapper says. This work has been used for treating graft-versus-host disease in patients who have undergone bone marrow transplants, but studies in mice suggest it could be an effective treatment for IBD as well.

Applying Lab Findings to Clinical Trials

At the 2021 Digestive Disease Week conference, Dr. Snapper and Brigham colleagues including Jessica R. Allegretti, MD, MPH, Vanessa Mitsialis, MD, Matthew J. Hamilton, MD, and Joshua R. Korzenik, MD, presented the results from an open-label, single-arm, phase 1b/2a trial that looked at whether subcutaneously administered, low-dose interleukin-2 is safe and results in a biological response. The study, which enrolled 26 patients with ulcerative colitis, showed that this treatment was well-tolerated, and was associated with a biological response and the expansion of regulatory T cells in patients with moderate to severely active ulcerative colitis.

“This treatment led to clinical improvement in more than 50% of the patients and complete remission in about a quarter of them,” Dr. Snapper says. “These are patients who had already failed multiple drugs.”

A new early-stage study has enrolled eight patients to look at whether expanding regulatory T cells with interleukin-2 can provide the same benefit in people with Crohn’s disease.

Outside of his clinical trials, Dr. Snapper was instrumental in establishing the Very Early Onset Inflammatory Bowel Disease (VEO-IBD) Consortium, an international group of investigators studying IBD in young children. The group includes scientists from North America, Europe, Australia, South America, Israel and the Middle East who are all focused on these efforts.

The VEO-IBD Consortium has identified numerous genetic defects that cause IBD and has developed novel therapeutic approaches. The group has received support from a number of philanthropies, including the Helmsley Charitable Trust and the National Institutes of Health, as well as support from the pharmaceutical and biotechnology industries.

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Blood Test Offers Better Prediction of Preeclampsia Risk

Source: Brigham and Women's Hospital
Date: 5/9/2022
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Improvement in rates of maternal morbidity and mortality has been limited by the inability to assess fetal and maternal tissues before symptoms develop. Thomas McElrath, MD, PhD, an obstetrician in the Division of Maternal-Fetal Medicine at Brigham and Women’s Hospital, Michal A. Elovitz, MD, of the University of Pennsylvania, and colleagues have shown in a publication in Nature that the patterns of cell-free RNA (cfRNA) from maternal plasma progress in a predictable gestational-age dependent fashion. As such, these molecular signatures can be used to survey the gestational age of the pregnancy as well as the overall wellbeing of mother, placenta and baby. The team demonstrated this concept by predicting the risk of preeclampsia, a hypertensive condition unique to pregnancy, on average 14 weeks prior to the development of symptoms.

Methods

The researchers measured cfRNA in 2,539 plasma samples drawn from 1,840 pregnant women of multiple ethnicities, nationalities, geographic locations and socioeconomic circumstances, while covering a range of gestational ages. This was the largest and most diverse dataset of maternal transcriptomes ever analyzed.

Measuring Gestational Age

The researchers first restricted their study to plasma samples from healthy pregnancies, building a machine learning model of normal cfRNA patterns in uncomplicated pregnancies. By design, these models also served to predict gestational age. A cfRNA signature was as accurate as second-trimester ultrasound and superior to third-trimester ultrasound while also providing insights into the biology of pregnancy progression.

Thus, the model could offer alternative dating for women who start prenatal care later in pregnancy. Its predictions were driven almost entirely by information from the cfRNA transcripts, as body mass index, maternal age and race accounted for less than 1% of the variance.

A Window into Maternal–Fetal Development

cfRNA profiles also made it possible to assess the molecular status of the placenta, fetal organs, cervix and uterus. Hundreds of independently identified gene sets in maternal blood mirrored the maternal and fetal physiological changes expected during pregnancy.

A study of three independent cohorts verified that multiple gene sets were uniquely associated with specific tissues of origin. These included the uterus and cervix as well as the placenta. Most intriguingly, however, the team also detected the unique signature of fetal tissues including fetal heart, GI tract and kidneys. Thus, the use of cfRNA signatures could reveal and characterize molecular changes in the maternal–fetal dyad during gestation.

Early Prediction of Preeclampsia

As an example of predicting adverse outcomes, the team evaluated the ability of cfRNA signatures in maternal blood during the second trimester to identify women at risk of preeclampsia. A case–control study included 72 women with preeclampsia and 452 without, selected from two independent cohorts.

Correlation tests identified signatures that separated the cases and controls and identified seven genes consistently associated with preeclampsia. A screening test based on those genes achieved a sensitivity of 75%, with an area under the receiver operating curve of 0.82.

The inclusion of maternal body mass index, age and race had no effect on the new test’s performance.

Women who tested positive delivered significantly earlier during gestation than women who tested negative. In addition, a positive test correctly identified 73% of women who had a medically indicated preterm birth—more than three months ahead of clinical symptoms or delivery.

Hypertension vs. Normotension

In pregnant women who have preexisting hypertension, it can be quite challenging to distinguish superimposed preeclampsia from exacerbation of hypertension. The difference is important because one requires delivery for a cure and the other usually doesn’t.

One of the cohorts used to estimate preeclampsia risk included 50 women with hypertension (chronic hypertension, n=31; gestational, n=19) and 263 normotensive women. Genes identified by comparing the two groups showed no overlap with genes significant for preeclampsia. Also, none of the genes were differentially expressed. Thus, the molecular signal for preeclampsia was specific to hypertension driven by a placental disorder.

Clinical Importance

Considering the large, diverse study population, it’s noteworthy that race had almost no effect on gestational age estimates or preeclampsia risk evaluation. Including race in clinical risk assessment has been shown in several fields to be problematic, have little or no utility, and in fact represent a source of latent bias against members of underrepresented minority communities. In contrast, the cfRNA signature directly exposes the development of preeclampsia.

A better understanding of the maternal–fetal–placental transcriptome should lead to precision therapeutic interventions that can target molecular subtypes of preeclampsia and preterm birth.

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Researchers Probe Links Between Colorectal Cancer, Bariatric Surgery

Source: Brigham and Women's Hospital
Date: 4/26/2022
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The microbiota, the collective term for all the microorganisms living in the body, has been called the “forgotten organ” for its broad influence across many bodily systems. But in recent years, increased research focused on the microbiota—and the gut microbiota in particular—has meant that it’s not quite so forgotten anymore.

Investigators at Brigham and Women’s Hospital are undertaking a new project to look at the link between the microbiota and colorectal cancer. By harnessing unique partnerships among members of the Laboratory for Surgical and Metabolic Research, which includes many physician-scientists from the Division of General and Gastrointestinal Surgery, researchers hope to learn more about this connection. This includes taking a closer look at how bariatric surgery changes the microbiome along with the impact this connection may have on the development of colorectal cancer.

“We know that obesity and bariatric surgery are both on the rise,” says James Yoo, MD, a member of the Section of Colon and Rectal Surgery at the Brigham, who is co-leading the new research initiative. “In addition, colorectal cancer is one of the most common cancers in the world. The first step of this research is to try to understand some of the mechanisms that may connect the two.”

Looking at Complicated Connections

The aim of bariatric surgery is to alleviate obesity, a known risk factor for colorectal cancer and other cancers. “But although there is a lot of evidence in the literature that bariatric surgery and weight loss reduce the risk for more types of cancer, findings from studies looking at this connection for colorectal cancer, in particular, have been mixed,” says surgeon Eric G. Sheu, MD, PhD, who is the other co-leader of the research initiative. “Some studies have suggested that bariatric surgery may actually increase the risk of colorectal cancer.”

To get at the heart of this mystery, the team has turned to mouse models of bariatric surgery that had previously been established in the lab. Obese mice are treated with a gastric sleeve procedure similar to the one used in humans. Their feces are collected before and after the procedure and their microbiota are analyzed. (The same can be done in humans.)

“There are some specific types of changes in the microbiota we’ve observed that are consistent after bariatric surgery in both mice and patients,” Dr. Sheu says. “We’re working to understand which groups of organisms may mediate these changes on the microbe side and exactly what the changes are on the host side.”

Once these connections are made, one outcome of this research may be using certain strains or microbial signatures as a biomarker to determine which patients might need to be monitored more closely for the development of colorectal cancer after their bariatric surgery. According to Dr. Sheu, he and his colleagues are not able to narrow the connection down to particular strains. Rather, they are focused on trying to understand the mechanisms that may be involved.

Collaboration Enables Unique Studies

Collaboration is important not only for this research but for the work of the Laboratory for Surgical and Metabolic Research more broadly. The lab has several active areas of investigation involving animal models of surgery and translational studies of patients and patient samples.

In his other work, Dr. Yoo examines the molecular mechanisms in colorectal cancer signal transduction, which includes studying colitis-associated cancers. Dr. Sheu’s other research focuses on understanding the role of immunometabolism and the microbiome in type 2 diabetes resolution after bariatric surgery.

“The members of our lab are very collaborative, which allows for a lot of cross-specialty interactions,” Dr. Yoo says. “There’s a lot of research firepower at the Brigham, and being able to access all these resources and bring together people with seemingly different specialties allows us to address these complicated problems that would be difficult to tackle elsewhere.”